SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging.

Fibrosis is a typical aging-related pathological process involving almost all organs, including the heart, kidney, liver, lung, and skin. Fibrogenesis is a highly orchestrated process defined by sequences of cellular response and molecular signals mechanisms underlying the disease. In pathophysiologic conditions associated with organ fibrosis, a variety of injurious stimuli such as metabolic disorders, epigenetic changes, and aging may induce the progression of fibrosis. Sirtuins protein is a kind of deacetylase which can regulate cell metabolism and participate in a variety of cell physiological functions. In this review, we outline our current understanding of common principles of fibrogenic mechanisms and the functional role of SIRT3/6 in aging-related fibrosis. In addition, sequences of novel protective strategies have been identified directly or indirectly according to these mechanisms. Here, we highlight the role and biological function of SIRT3/6 focus on aging fibrosis, as well as their inhibitors and activators as novel preventative or therapeutic interventions for aging-related tissue fibrosis.

A 2D Ba2N Electride for Transition Metal-Free N2 Dissociation under Mild Conditions.

N2 activation is a key step in the industrial synthesis of ammonia and other high-value-added N-containing chemicals, and typically is heavily reliant on transition metal (TM) sites as active centers to reduce the large activation energy barrier for N2 dissociation. In the present work, we report that a 2D electride of Ba2N with anionic electrons in the interlayer spacings works efficiently for TM-free N2 dissociation under mild conditions. The interlayer electrons significantly boost N2 dissociation with a very small activation energy of 35 kJ mol-1, as confirmed by the N2 isotopic exchange reaction. The reaction of anionic electrons with N2 molecules stabilizes (N2)2- anions, the so-called diazenide, in the large interlayer space (∼4.5 Å) sandwiched by 2 cationic slabs of Ba2N as the main intermediate.

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

Boosted Activity of Cobalt Catalysts for Ammonia Synthesis with BaAl2O4-xHy Electrides.

Electrides are promising support materials to promote transition metal catalysts for ammonia synthesis due to their strong electron-donating ability. Cobalt (Co) is an alternative non-noble metal catalyst to ruthenium in ammonia synthesis; however, it is difficult to achieve acceptable activity at low temperatures due to the weak Co-N interaction. Here, we report a novel oxyhydride electride, BaAl2O4-xHy, that can significantly promote ammonia synthesis over Co (500 mmol gCo-1 h-1 at 340 °C and 0.90 MPa) with a very low activation energy (49.6 kJ mol-1; 260-360 °C), which outperforms the state-of-the-art Co-based catalysts, being comparable to the latest Ru catalyst at 300 °C. BaAl2O4-xHy with a stuffed tridymite structure has interstitial cage sites where anionic electrons are accommodated. The surface of BaAl2O4-xHy with very low work functions (1.7-2.6 eV) can donate electrons strongly to Co, which largely facilitates N2 reduction into ammonia with the aid of the lattice H- ions. The stuffed tridymite structure of BaAl2O4-xHy with a three-dimensional AlO4-based tetrahedral framework has great chemical stability and protects the accommodated electrons and H- ions from oxidation, leading to robustness toward the ambient atmosphere and good reusability, which is a significant advantage over the reported hydride-based catalysts.

To Investigate the Clinical Efficacy and Potential Mechanism of Tongxinluo Capsules in Preventing Coronary Restenosis Based on Meta-Analysis and Network Pharmacology Analysis.

Objective: The aim of this study is to evaluate the clinical efficacy of Tongxinluo capsules in preventing coronary restenosis based on meta-analysis and network pharmacology research methods and to preliminarily explore its intervention mechanism. Methods: First, through meta-analysis, we comprehensively searched databases such as CNKI, Wanfang, PubMed, the Cochrane Library, and Web of Science to find out the randomized controlled trials of Tongxinluo capsules in the treatment of coronary restenosis until February, 2022. According to the Cochrane Library, risk bias assessment tools were used to evaluate the included literature and Review Manager 5.2 software was used to conduct statistical analysis of the included studies. Then, based on network pharmacology, through TCMSP database and BATMAN-TCM database screening, the chemical components of Tongxinluo capsules and their related effects, symptom, and common targets were analyzed. String net was used to construct protein-protein interaction (PPI) network, and R3.6.1 software was used to carry out GO biological process enrichment analysis and KEGG signaling pathway enrichment analysis to clarify key pathways. Results: The meta-analysis finally included 10 RCTs with a total of 1318 subjects. Meta-analysis results showed that Tongxinluo capsules combined with conventional cardiovascular drugs could significantly improve the clinical efficacy of preventing in-stent restenosis and the clinical efficacy of preventing angina pectoris. There was no significant difference in the clinical efficacy of preventing myocardial infarction. Network pharmacology obtained a total of 101 chemical components and 149 targets through the online database. The results of network analysis showed that the targets were mainly involved in receptor ligand activity, carboxylic acid binding, steroid hormone receptor activity, and other related action pathways and were also involved in AGE-RAGE signaling pathway, cell senescence signaling pathway, and other related pathways. Conclusion: Tongxinluo capsules combined with conventional cardiovascular drugs can improve the clinical efficacy of preventing in-stent restenosis and angina pectoris and have a significant effect on reducing inflammatory factors. The comprehensive result of the effect is mainly through the participation of receptor ligand activity, carboxylic acid binding, steroid hormone receptor activity, and other ways to achieve the purpose of treating coronary restenosis.

Urban Shrinkage and Urban Vitality Correlation Research in the Three Northeastern Provinces of China.

In the global trend of urban shrinkage, urban vitality, as one of the important representations of high-quality urban development, has become a breakthrough. More and more scholars advocate to awaken urban vitality, so as to realize the high-quality development of shrinking cities. This paper takes the municipal districts of 34 cities in the three northeastern provinces of China as study areas, based on the broad concept of urban shrinkage, selects the indicators of population, economy and society, and uses the "two-step diagnostic method" which is consistent with Chinese conditions to identify the urban shrinkage from 2010 to 2018. In this research, the indexes of economic, social, cultural, environmental and spatial dimensions are selected, and the urban vitality and the vitality of each dimension from 2010 to 2018 are calculated and analyzed by using the entropy weight method (EWM). Then, this paper analyzes the correlation between urban shrinkage and urban vitality by Pearson correlation coefficient. The results show that: (1) urban shrinkage in the three northeastern provinces of China has become a regional remarkable phenomenon, which is also an inevitable process in some regions of China and even the world; (2) overall, the urban vitality of cities in the three northeastern provinces of China is steady and rising a little, and there is an obvious spatial agglomeration pattern like "central city polarization"; (3) there is a significant correlation between urban shrinkage and urban vitality, that is, the lower the degree of urban shrinkage, the higher the urban vitality, showing the opposite trend in the process of urban development; (4) the influence of urban shrinkage on each dimension of urban vitality is different, and the correlation results are different, too. In the planning process of shrinking cities in the future, paying attention to the relationship between urban vitality and urban shrinkage, conducting benign guidance on this basis, and adjusting urban vitality elements of different dimensions to stimulate urban development power can enhance urban competitiveness and achieve better development.

Exploring a Multi-Layer Coupled Network Propagation Model Based on Information Diffusion and Bounded Trust.

Objective: To explore the law of opinion dissemination and individual opinion evolution at the micro level, this paper analyzes the influence of variation and oyster on communication from the perspective of network structure. Methods: In this paper, we introduce the concepts of "variation" and "oyster", build a multi-layer coupled network environment combined with the ISOVR model, and conduct simulation experiments of network information dissemination based on the bounded trust model. Results: The experimental results reveal that the extent and scope of variation's spread in the network are more dependent on the trust of nodes themselves, and decreasing the trust of nodes significantly reduces the rate and peak value of variation. Changing the silence coefficient of variation does not effectively change the direction of rumor propagation, which indicates that rumor has a strong propagation ability after mutation. Conclusion: The insights of this paper on the dissemination of public opinions include: 1) pay attention to people with high trust levels, such as opinion leaders; 2) clarify the misinformation in time to prevent further spread of rumors.

Online Rumor Diffusion Model Based on Variation and Silence Phenomenon in the Context of COVID-19.

In the era of mobile internet, information dissemination has made a new leap in speed and in breadth. With the outbreak of the coronavirus disease 2019 (COVID-19), the COVID-19 rumor diffusion that is not limited by time and by space often becomes extremely complex and fickle. It is also normal that a piece of unsubstantiated news about COVID-19 could develop to many versions. We focus on the stagnant role and information variants in the process of rumor diffusion about COVID-19, and through the study of variability and silence in the dissemination, which combines the effects of stagnation phenomenon and information variation on the whole communication system in the circulation of rumors about COVID-19, based on the classic rumor SIR (Susceptible Infected Recovered) model, we introduce a new concept of "variation" and "oyster". The stability of the new model is analyzed by the mean field equation, and the threshold of COVID-19 rumor propagation is obtained later. According to the results of the simulation experiment, whether in the small world network or in the scale-free network, the increase of the immure and the silent probability of the variation can effectively reduce the speed of rumor diffusion about COVID-19 and is conducive to the dissemination of the truth in the whole population. Studies have also shown that increasing the silence rate of variation can reduce COVID-19 rumor transmission more quickly than the immunization rate. The interesting discovery is that at the same time, a higher rumor infection rate can bring more rumors about COVID-19 but does not always maintain a high number of the variation which could reduce variant tendency of rumors. The more information diffuses in the social group, the more consistent the version and content of the information will be, which proves that the more adequate each individual information is, the slower and less likely rumors about COVID-19 spread. This consequence tells us that the government needs to guide the public to the truth. Announcing the true information publicly could instantly contain the COVID-19 rumor diffusion well rather than making them hidden or voiceless.

Preparation of Giant Escherichia coli spheroplasts for Electrophysiological Recordings.

Prokaryotic ion channels have been instrumental in furthering our understanding of many fundamental aspects of ion channels' structure and function. However, characterizing the biophysical properties of a prokaryotic ion channel in a native membrane system using patch-clamp electrophysiology is technically challenging. Patch-clamp is regarded as a gold standard technique to study ion channel properties in both native and heterologous expression systems. The presence of a cell wall and the small size of bacterial cells makes it impossible to directly patch clamp using microelectrodes. Here, we describe a method for the preparation of giant E. coli spheroplasts in order to investigate the electrophysiological properties of bacterial cell membranes. Spheroplasts are formed by first inhibiting bacterial cell wall synthesis, followed by enzymatic digestion of the outer cell wall in the presence of a permeabilizing agent. This protocol can be used to characterize the function of any heterologous ion channels or ion transporters expressed in E. coli membranes.

Activation of the archaeal ion channel MthK is exquisitely regulated by temperature.

Physiological response to thermal stimuli in mammals is mediated by a structurally diverse class of ion channels, many of which exhibit polymodal behavior. To probe the diversity of biophysical mechanisms of temperature-sensitivity, we characterized the temperature-dependent activation of MthK, a two transmembrane calcium-activated potassium channel from thermophilic archaebacteria. Our functional complementation studies show that these channels are more efficient at rescuing K+ transport at 37°C than at 24°C. Electrophysiological activity of the purified MthK is extremely sensitive (Q10 >100) to heating particularly at low-calcium concentrations whereas channels lacking the calcium-sensing RCK domain are practically insensitive. By analyzing single-channel activities at limiting calcium concentrations, we find that temperature alters the coupling between the cytoplasmic RCK domains and the pore domain. These findings reveal a hitherto unexplored mechanism of temperature-dependent regulation of ion channel gating and shed light on ancient origins of temperature-sensitivity.

Dynamics and number of trans-SNARE complexes determine nascent fusion pore properties.

The fusion pore is the first crucial intermediate formed during exocytosis, yet little is known about the mechanisms that determine the size and kinetic properties of these transient structures. Here, we reduced the number of available SNAREs (proteins that mediate vesicle fusion) in neurons and observed changes in transmitter release that are suggestive of alterations in fusion pores. To investigate these changes, we employed reconstituted fusion assays using nanodiscs to trap pores in their initial open state. Optical measurements revealed that increasing the number of SNARE complexes enhanced the rate of release from single pores and enabled the escape of larger cargoes. To determine whether this effect was due to changes in nascent pore size or to changes in stability, we developed an approach that uses nanodiscs and planar lipid bilayer electrophysiology to afford microsecond resolution at the single event level. Both pore size and stability were affected by SNARE copy number. Increasing the number of vesicle (v)-SNAREs per nanodisc from three to five caused a twofold increase in pore size and decreased the rate of pore closure by more than three orders of magnitude. Moreover, pairing of v-SNAREs and target (t)-SNAREs to form trans-SNARE complexes was highly dynamic: flickering nascent pores closed upon addition of a v-SNARE fragment, revealing that the fully assembled, stable SNARE complex does not form at this stage of exocytosis. Finally, a deletion at the base of the SNARE complex, which mimics the action of botulinum neurotoxin A, markedly reduced fusion pore stability. In summary, trans-SNARE complexes are dynamic, and the number of SNAREs recruited to drive fusion determines fundamental properties of individual pores.

Camphor Tree Seed Kernel Oil Reduces Body Fat Deposition and Improves Blood Lipids in Rats.

The total and positional fatty acid composition in camphor tree (Cinnamomum camphora) seed kernel oil (CKO) were analyzed, and for the first time, the effect of CKO on body fat deposition and blood lipids in rats was studied. The major fatty acids in CKO were determined to be decanoic acid (C10:0, 51.49%) and dodecanoic acid (C12:0, 40.08%), and uniformly distributed at Sn-1, 3, and Sn-2 positions in triglyceride (TG). Rats were randomly divided into control, CKO, lard, and soybean oil groups. At the end of the experiment, levels of blood lipids and the fats of abdomen in the rats were measured. The main organ were weighted and used for the histological examination. The results showed that body weight and fat deposition in CKO group were significantly lower than the lard and soybean groups. Moderate consumption of CKO was found to improve the levels of blood TG and low density lipoprotein cholesterol.

The effects of Fructus Aurantii extract on the 5-hydroxytryptamine and vasoactive intestinal peptide contents of the rat gastrointestinal tract.

CONTEXT: Fructus Aurantii, the unripe fruit of Citrus aurantium Linn (Rutaceae), is a Qi-regulating drug used in traditional Chinese medicine to improve gastrointestinal (GI) function. Vasoactive intestinal peptide (VIP) and 5-hydroxytryptamine (5-HT) regulate GI motility and fluid secretion. OBJECTIVE: We tested whether the Fructus Aurantii extract altered VIP and 5-HT expression levels in rats. MATERIALS AND METHODS: Experimental rats were administered 0.3 g/ml Fructus Aurantii water decoction at 2.0 ml/100 g body weight per day for 10 days by gavage feeding, while control rats were gavage fed equal volumes of distilled water. Expression levels of 5-HT and VIP were measured by immunohistochemical staining and microscopic image analysis of the GI mucosa and myenteric nerve plexus. RESULTS: Average 5-HT staining intensity scores in the stomach antrum, duodenal mucosa and jejunal mucosa were significantly higher in the Fructus Aurantii treatment group than in the control group (antrum: 213% of control; duodenum: 193%; jejunum: 256%; p < 0.05 for all). In contrast, the average VIP density scores in the stomach antrum, duodenal mucosa and jejunal mucosa were significantly lower in the Fructus Aurantii group (antrum: 14% of control; duodenum: 15%; jejunum: 38%; p < 0.01 for all). Tissues from Fructus Aurantii-treated rats exhibited significantly greater numbers of 5-HT- and VIP-immunopositive cells in the gastric antrum, duodenum and jejunum mucosal layer but fewer VIP-expressing cells in the myenteric nerve plexus (p < 0.05 for both). CONCLUSION: Fructus Aurantii can enhance gastrointestinal motility by altering 5-HT and VIP expression levels in the rat GI tract.

Probucol inhibits hydrogen peroxide to induce apoptosis of vascular smooth muscle cells.

The aim of this study was to investigate the effect of the antioxidant probucol on hydrogen peroxide (H2O2)-induced vascular smooth muscle cell (VSMC) apoptosis. H2O2 (1 mmol/l) was used as the VSMC apoptosis-inducing agent, and 100, 10 and 1 µmol/l probucol concentrations were incubated with cells for 6 h. The cell apoptosis was observed using Annexin V-FITC, TUNEL and Hoechst 33258 staining methods. H2O2 promoted VSMC apoptosis, ASK-1 protein expression increased and Trx-l protein expression decreased. Probucol reduced H2O2-induced apoptosis in a dose-dependent manner; while ASK-1 protein expression decreased, Trx-1 protein expression increased. Probuco1 is capable of antagonizing the H2O2-induced apoptosis in VSMCs, which may be related to the decrease in ASK-1 protein expression and the increase in Trx-1 protein expression.

[Determination of 6 kinds of pesticides residue in Dioscoreae rhizoma slices by GC-MS].

OBJECTIVE: To determine the 6 residues including organophosphorus, organochlorinated and pyrethroid pesticides simultaneously in crude yam slices, yam slices stir-fried with bran and sulfur fumigation yam. METHODS: The compounds were ready for GC-MS analysis after being extracted with acetonitrile and purified. Determinations were performed with selected ion monitoring mode and external standard method was adopted in the quantificaticon. RESULTS: The contents of 6 kinds pesticides residue had good linear correlation with the peak area in the rang of 0.01-0.5 microg/mL. The average recoveries of 6 kinds pesticides residue were 87.5%-95.5%. The method detection limits ranged from 0.002-0.005 microg/g. Organochlorine and pyrethroid pesticides were detected in the three samples except the parathion residue. CONCLUSION: Stir-fried with bran and sulphur fumigation had nearly no effects on the pesticides residue in yam. The method is sensitive and accurate and can be used in determination of multiresidual pesticides residue in yam.

[Analysis of volatile oil in Fructus Aurantii processed with Zhangband method by GC-MS].

OBJECTIVE: To analyze the chemical components of the volatile oil in processed pieces of Fructus Aurantii (PPFA) with JiangXi Zhangband methods by GC-MS. METHODS: The volatile oil was obtained from PPFA by steam distillation. The amount of the components from the volatile oil were determinated by area normalization method. The separated components were identified by GC-MS. RESULTS: Composed of the total volatile oil over 90% , 70 components were separated and identified. All of the processed Fructus Aurantii produced new chemical composition, in the meantime,the contents were changed in some chemical composition after processed. CONCLUSION: The method is reliable, stable and has good repeatability. This method can be applied to the analysis of volatile oil components in PPFA. It will provide the certain scientific methods for further evaluating of PPFA quality.

[HPLC determination of strychnine and brucine in Semen Strychni and its processed products].

OBJECTIVE: This paper reports a HPLC method for determinition of strychnine and brucine in Semen Strychni and its processed products of Jiangxi method and innovated methed. METHOD: SiO2 was used as the stationary phase, n-hexane-dichloromethane-methanol-ammonia(47.5:47.5:5:0.35) as the mobile phase, with detection wavelength of 254 nm. RESULT: The contents of strychnine and brucine in the processed products of Jiangxi are lower. CONCLUSION: This method is accurate, simple and reliable.